Ortho (3, 5-diiodo benzyl)-and ortho (3, 5-diiodo benzoyl)-benzoic acids



UNITED STATES PATENT OFFICE ORTHd (3,5-DIIODO BENZYL)- AND ORTHO 3,5-DIIODO BENZOYL) -BENZOIC ACIDS William H. Strain, Rochester, N. Y., assignor to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana 7 No Drawing. Application November 27, 1948, Serial No. 62,407

8 Claims. (Cl. 260-517) My invention relates to cholecystographic of my invention may be represented by the folagents and more particularly to a group of sublowing formula stituted benzoic acids and salts having utility as I X-ray contrast agents.

In the practice of cholecystography, compounds 6 possessing opacity to X-rays are administered 1 I either orally or intravenously prior to the time Coon at which the radiographic study is to be made. During the interval before radiographic study, the compounds localize in the gall bladder so wherein 1' represents a methylene (.-CH2) or 10 carbonyl that the bladder becomes opaque to X-rays and 0 hence may be selectively delineated by means JL of X- y radical, and one 3 is hydroxyl (-OH), the other one Whlch been Widely used being hydrogen (-H), and R represents hydrofor radwgraphlc purposes is tetralodophenol' 1 gen or a metallic radical such as an alkali, alphthalein The use of this compound however kaline-earth or ammonium radical which forms is attended by several drawbacks. When tetraa water soluble Salt with the acid. The iodophenolphthalein is administered orally the pounds of my invention, therefore are iodinated compound usually produces nausea and diarrhea, hydroxybenzybbenzoic acids and iodinated and frequently adsorbed so poorly that droxybenzoyl-benzoic acids, and their salts.

fusing shadows persistm the bowel to s a The compounds represented above are colordegree that the g blaqder shadow. is masked less solids. The acids have a low water solubility Intravenous administratmn of tetraiodophenolbut the salts containing the common metallic phthalein avoids some of the disadvantages acradicals Such as sodium potassium ammoniu companying oral administration but is disadand the like are readilywatebsolugle vantageous in that hospitalization of the patient The novel acids of this invention are prepared and highly trained personnel are required for by iodination of the appropriate hydroxybenzyl productlon 0f Satlsfactory resultsbenzoic acid or hydroxybenzoyl acid, the iodinaof recent years 5' tion being carried out with iodine monochloride Y1) acid has P or with iodine-potassimn iodide mixture. The as cholecystographm agent Thls agen? avolds salts of the iodine-containing benzoic acids are some of h dlsadvantages .accompanymg the prepared by treating the acids with an equivalent use of tetralodophenolphthalem but, on the other amount of base or a basic salt Such as a cab hand, markedly inhibits the motor function of bonate or bicarbonate Salt.

the gall bladder and furtherm9re the results The administration of my compounds for radioobtained are diagnostically unreliable when poor graphic Work may be oral or intravenous Oral fi ll1ng of the gall bladder occurs so that only a administration preferably is carried out with hght Shadow 18 Obtained Addltlonany p the free acids, and desirably the acids before ant side effects such as nausea and the like are administration are finely commmuted, i. e, encountered in a significant percentage of the 40 micronized The commmuted materi a1 may Patients to Whom h m u is administered be given as a powder, or administered in cap- An Objecfi of my mveptwn 15 to Provlde 1 sules, or may be mixed with a suitable binder cystoglaphlc agents Whlch are free from the C115 and formed into a tablet prior to administration.

advantageous propertles P the compwnds, of Since the acids themselves are either tasteless the Prior 9111- other oblects of my mventlon or possess a sweet taste, there is no need of will be apparent from the following disclosuresimultaneous administration of agents such as In accordance With the above and other chocolate and the like which are frequently used i ts I av p d h y sr p i a ents to mask unpleasant tastes. For intravenous adcomprising a group of substituted benzoic acids ministration, water-soluble salts in aqueous and their water-soluble salts. The compounds 59 solution are employ d, the sodium salt being the in excellent salt of choice. The dosage required for gall bladder visualization varies somewhat with the size of the patient but a dose in the range of 2 to 4 g. will give satisfactory delineation when the usual cholecystographic techniques are employed.

My novel compounds when administered in accordance with the customary practices are capable of giving excellent radiographic results, and thus are of great value in the diagnostic armamentarium. Their affinity for the gall bladder is so marked that delineation of the bladder is obtained in a relatively short time. Experiments in dogs have shown that intravenous administration of my compounds, for example sodium (4-hydroxyl-3,5-diiodobenzyl) -benz0- ate, produces a good visualization of the gall bladder in 20 minutes, Whereas comparable visualization with fi-(4-hydroxy-3,5-diiodophenyl) -a-phenylpropionic acid and tetraiodophenolphthalein is obtained only after a much longer period of time. Administration to human patents has produced no nausea as is usually experienced with tetraiodophenolphthalein or commonly observed with B-(4-hydroxy-3,5-diiodophenyl) uphenylpropionic acid. Furthermore, no untoward efiect'on the function of the gall bladder has been observed. More surprisingly, I have found that not only is the gall bladder delineated but also the extrahepatic biliary ducts are made visible. A ready duct visualization cannot be achieved by means of the other cholecystographic agents now employed.

My invention is further illustrated by the following specific examples which describe methods of preparing representative benzoic acids and salts within the scope of my invention.

Example 1 is prepared as follows:

A solution of 43 parts of o- (-hydroxybenzoyl) benzoic acid dissolved in 1000 parts of warm glacial acetic acid is treated with a solution of 110 parts of iodine monochloride in acetic acid. After mixing is complete, 1000 parts of warm water are added and the mixture is heated to about 80-90 C. for half an hour. After heating, the reaction mixture is poured into a large volume of cold water and the excess iodine is destroyed by the addition of a small amount of sodium sulfite. The o-(4-hydroxy-3,5-diiodobenzoyl)- benzoic acid which has precipitated is filtered off, washed well with water and dried. o-(4-hydroxy-3,5-diiodobenzoyl) -ben zoic acid is obtained yield as a white powder of high purity. It is further purified by crystallization from dilute alcohol. Pure o-(4-hydroxy-3,5- diiodobenzoyl) -benzoic acid melts at about 223 C.

The sodium salt of o-(4-hydroxy-3,5-diiodo benzoyl) -benzoic acid is obtained by treating an aqueous suspension of the acid with an equivalent amount of sodium hydroxide. The salt is isolated by evaporating the solution to dryness. Alternatively, the salt can be isolated by reducing the volume of the aqueous solution and adding an excess of acetone to cause precipitation of the salt.

Example 2 acid is prepared as follows:

To a solution prepared from 228 parts of o-(4- hydroxybenzyl) -benzoic acid, 400 parts of water and 400 parts of concentrated ammonium hydroxide, are added 2500 parts of crushed ice. To the mixture is added with mechanical stirring and at such a rate that the temperature does not rise above 0 C., a solution comprising a mixture of 508 parts of potassium iodide, 508 parts of iodine and 3000 parts of water. After the iodine solution is added the reaction mixture is stirred for 15 minutes, and 5 parts of sodium sulfite are added to destroy any excess iodine. To the mixture are added 6000 parts of hot (50 C.) water, and the mixture is acidified by the addition of dilute sulfuric acid. The acidified mixture is stirred for 10 minutes. The o-(4-hydroxy-3,5- diiodobenzyD-benzoic acid which precipitates is filtered oif and washed with water until free from mineral acid. The moist o-(4-hydroxy3,5-di iodobenzyl) -benzoic acid is stirred with about 10 volumes of water, and dissolved by the addition to the mixture of a solution comprising 84 parts of sodium hydroxide dissolved in 400 parts of water and finally 42 parts of dry sodium bicarbonate. After evolution of carbon dioxide has ceased, 5 parts of sodium sulfite and 30 parts of decolorizing carbon are added and the mixture is stirred for 30 minutes and. filtered. The filtrate is diluted with an equal volume of hot water and acidified by the addition of dilute sulfuric acid. The o-(4-hydroxy-3,5-diiodobenzyl) -benzoic acid which precipitates upon acidification, is'filtered off, Washed with water and dried. o-(4-hydroxy- 3,5-diiodobenzyD-benzoic acid thus prepared is obtained in excellent yield. It melts at about 208-209 C.

The sodium salt of o-(4-hydroxy-3,5-diiodobenzyl) -benzoic acid can be repared by adding to an alcoholic solution of the acid, an equivalent amount of sodium ethoxide dissolved in alcohol, and filtering off the sodium o-(4-hydroxy-3.5- diiodobenzyl) -benzoate which precipitates.

Example 3 Preparation of o-(4-hydroxy-3,5diiodobenzyl) -benzoic acid.

o-( i-hydroxy 3,5 diiodobenzyl) -benzoic acid may also be prepared from 6-8 parts of o-(4- hydroxybenzyD-benzoic acid dissolved in 1000 parts of warm glacial acetic acid by the iodination technique described in Example 1. The 0- (4-hydroxy-3,5-diiodobenzyl) benzoic acid is obtained in good yield as a fawn colored product and is purified by crystallization from ethyl alcohol or acetic acid.

Example 4 Preparation of o-(2-hydroxy-3,5-diiodobenzoyl) -benzoic acid.

o-(2-hydroxy 3,5-diiodobenzoyl-benzoic acid represented by the following formula OH I I COOH is prepared as follows:

A solution of 73 parts of o-(2-hydroxybenzoyl) benzoic acid dissolved in 1000 parts of warm glacial acetic acid is iodinated according to the procedure described in Example 1. The o-(2-hydroxybenzoyD-benzoic acid is obtained in good yield as a white powder. It is purified by crystal lization from dilute alcohol, and is obtained in the form of white crystals which melt at about 216- 218 C.

Example 5 Preparation of o- (2-hydroxy-3,5-diiodobenzy1) benzoic acid.

(2-hydroxy-3,5-diiodobenzyl) -benzoic represented by the formula OH I acid

COOH

is prepared by iodinating a solution of 68 parts of o- (Z-hydroxybenzyl) -benzoic acid in 1000 parts of warm glacial acetic acid according to the procedure described in Example 1. The o-(2- hydroxy-3,5-diiodobenzyl)-benzoic acid is obtained in good yield as a tan colored product. It is purified by crystallization from. acetic acid and when so purified is obtained as white crystals melting at 200-201 C.

Example 6 The salts of the acids described in Examples 3, 4 and 5 are obtained by the procedures for preparing salts described in Examples 1 and 2.

I claim:

1. A member of the acid represented by the group consisting of an following formula 6 3. A compound selected from the group consisting of 1 COOH and its salts with alkali-forming inorganic cat- 0 ions. 1 4. An alkali metal salt of an acid represented by the following formula I CHz-OOH l5 1 CODE 5. The compound represented by the following formula I CHrQ-OH I COONa 6. An alkali metal salt of an acid represented by the following formula I CODE 7. The compound represented by the following formula 0 I I COONa 8. o-(hydroxy-3,5-diiodobenzoyl) -benzoic acid. References Cited in the file of this patent UNITED STATES PATENTS Number Name Date 2,212,056 Tinker et a1 Aug. 20, 1940 2,345,384 Dohrn et al. Mar. 28, 1944 2,400,433 Natelson et al. May 14, 1946 OTHER REFERENCES and its alkali metal, alkaline-earth metal and ammonium salts, in which at represents a radical of the group consisting of the methylene and carbonyl radicals, and one y represents 'OH and the other represents H.

2. o- (4 hydroxy 3,5 diiodobenzyl) benzoic acid.

Orndorfi et 9.1., 1518-27 (1922).

Jones et al., Chem. Abstracts, vol. 42, col. 7938 (1948).

Jones et aL, (1948).

J. Am. Chem. 800., vol. 44,

Radiology, vol. 51, pp. 225-236 

1. A MEMBER OF THE GROUP CONSISTING OF AN ACID REPRESENTED BY THE FOLLOWING FORMULA 